Ovarian cancer is one of the most common causes of cancer death from gynecologic malignancy in the industrialized world. Standard treatment involves aggressive cytoreductive (debulking) surgery followed by chemotherapy. Ovarian cancer may spread to the lining of the abdominal cavity as intraperitoneal metastases (carcinomatosis) and leads to ascites. In general, carcinomatosis and ascites indicate a more advanced stage of the disease that usually requires extensive high dose chemotherapy (Berkenblit et al. (2005) J. Reprod. Med., 50:426-438; Kawaguchi et al. (2005) Curr. Drug Targets Cardiovasc. Haematol. Disord., 5:39-64). Furthermore, tumor cells from malignant ascites are more invasive and resistant to chemotherapy when compared with primary ovarian tumors (Lane et al. (2010) J. Ovarian Res., 3:1; Tang et al. (2010) Neoplasia 12, 128-138; Veatch et al. (1994) Int. J. Cancer 58:393-399). The precise mechanisms underlying the formation of ascites in ovarian cancer are unknown. However, it is known that the success of chemotherapeutic treatment of primary ovarian cancer and especially tumor cells growing in ascitic fluid is limited by the intrinsic and acquired resistance of cancer cells to chemotherapy (Lane et al. (2010) J. Ovarian Res., 3:1; Tang et al. (2010) Neoplasia 12, 128-138; Veatch et al. (1994) Int. J. Cancer 58:393-399; Li et al. (2009) BMC Cancer 9:323). Such resistance requires the use of multiple chemotherapeutic agents thus increasing the rate of severe adverse side effects of therapy on healthy organs and tissues.
The main mechanisms of multidrug resistance are common to most cancers and include “pump” and “nonpump” resistance (Liu et al. (1998) Gynecol. Oncol., 70:398-403; Minko et al. (2004) Curr. Drug Targets 5:389-406; Pakunlu et al. (2003) Pharm. Res., 20:351-359; Pakunlu et al. (2004) Cancer Res., 64:6214-6224; Krasznai et al. (2005) Anticancer Res., 25:1187-1192). Pump resistance is caused by membrane transporters that pump out the anticancer agents from cells, decreasing the intracellular drug concentration and thereby the efficacy of the treatment. The main mechanism of nonpump resistance is an activation of cellular antiapoptotic defense. Effective treatment of advanced multidrug resistant primary ovarian tumors and their intraperitoneal metastases may be possible only by suppressing simultaneously at least two main types of cellular resistance and by inducing cell death using several anticancer agents with different mechanisms of action. Such an objective can be best achieved if several anticancer agents are simultaneously delivered specifically to the tumor in combination with other active components that perform different functions for enhancing cellular uptake and efficiency of drugs in cancer cells, limiting adverse side effects, and preventing the development of drug resistance and metastases.